A major goal of the neuroscience community is to develop neuroprotective treatments that will slow or forestall the progression of chronic neurodegenerative diseases. Recent advances in the understanding of the pathogenesis of Parkinson's disease (PD),including the development of relevant animal models, provide the opportunity for rationale clinical trials to assess neuroprotective treatments. This application proposes an academically based clinical trials coordination center to finalize study protocols, train clinical centers, receive and manage all clinical trial data, maintain quality and regulatory standards, and organize packaging and delivery of experimental treatments to clinical centers. This Coordination Center will maintain an administrative structure that fosters close collaboration among, the Statistical center, clinical centers, NINDS Scientific Program personnel and an NIH Oversight Committee. Additional proposals include a rational process to select potential neuroprotective agents that will maximize the likelihood of successful choices, designs for pilot safety tolerability and dosage ranging studies, and the design for a large simple clinical trial to assess the impact of interventions on PD progression. The new onset of postural instability, one of the cardinal clinical signs of PD and a robust predictor of morbidity and mortality, is proposed as the primary clinical measure of disease progression. In addition to being a core clinical feature of PD and being reliably measurable, postural instability is inherently resistant to short-term symptomatic amelioration by current PD medications. Three potential neuroprotective compounds are proposed, although the final selection of compounds will be based on deliberations with other investigators. An appropriate research infrastructure combined with relevant scientific expertise is in place to conduct the proposed studies of neuroprotective agents in PD.